Emerging evidence indicates the orexin system is a key regulator for reward and motivation. It has been demonstrated that orexins, and the orexin-1 receptor in particular, are involved in drug self-administration, drug-associated cue processing, reward, and stress responses during drug abstinence in drug-dependent animals. In contrast to behavioral studies development of OX1 selective ligands has not progressed. Ligand development for the orexin system thus far focused on selective OX2 antagonists and/or dual OX1/OX2 antagonists for sleep disorders such as insomnia. Conversely, only a small number of OX1 selective antagonists have been described and SB-334867 represents the only pharmacological tool that has been employed in evaluating the physiological role of OX1 specific pathways in vivo. Despite its high selectivity, SB- 334867 has undesirable bioavailability (10%) and stability, and high doses of SB-334867 (30mg/kg) have been shown to lead to unwanted side effects (abnormal posture and immobility) that confound interpretation of behavioral experiments. Moreover, small molecule orexin agonists have not been reported and the peptides orexin-A and B remain the only available OX1 agonists for research purposes. Orexin-A and B have relatively low potency at the orexin receptors (~ 50nM) and are either non-selective or slightly OX2 selective. In addition, peptides are susceptible to proteolysis, do not penetrate the blood brain barrier and therefore, are normally directly administrated into the CNS. Taken together, there is an unmet need for selective OX1 agonists and antagonists that will serve as tools to further facilitate understanding of OX1R pharmacology and the critical role orexins play in drug abuse and addiction. In this application, we plan to develop OX1 agonists and antagonists with improved potency, selectivity and pharmacokinetic properties using strategies including rational chemical synthesis, virtual screens and peptidomimetic development. PUBLIC HEALTH RELEVANCE: Emerging evidence suggests that orexin 1 receptors play a critical role in a variety of physiological processes including reward and motivation and therefore, represent a valuable target in medication development for the treatment of drug abuse and addiction. This project plans to develop potent and selective agonists and antagonists for this receptor. These ligands will serve as tools to probe the signaling mechanisms and in vivo function of this receptor and could expedite the ultimate development of novel therapies for the treatment of conditions mediated by orexin signaling including drug abuse and addiction.